Treatment of an injury, diseases and inflammations with pharmaceuticals, e.g., drugs, often involve subjecting the whole system to the toxicity and/or adverse effects of those pharmaceuticals rather than just the injured site. This is because drugs are often administered through ingestion rather than localized delivery. As such, if the medication affects or treats only a particular part or organ in the body, it is desirable to administer the medication to only that part or organ. Such localized delivery minimizes adverse effects on other non-targeted parts or organs and reduces waste of the medication as systemic administration often requires a higher dose to achieve the same effect as localized delivery. While localized delivery of therapeutic agents to the site of injury is often the most effective mode of treatment, current modes of drug delivery are associated with peak and trough drug release profiles while sustained drug release is desirable. While localized drug delivery devices and methods are presently available, there remain several limitations to these approaches.
Localized deliveries in the eye have been utilized. The eye is a unique organ because of its anatomical structure and intrinsic physiological and defense mechanisms. The smooth and wet mucosal surface of the eye, unlike other mucosal epithelia, is directly exposed to the external environment and is prone to injury, desiccation, and pro-inflammatory stimuli. Every year more than 2.5 million eye injuries occur and 50,000 people permanently lose part or all of their vision, and approximately 3.2 million women age 50 and over and 1.68 million men age 50 and over are affected by dry eye syndrome (Eye health statistics at a glance, Compiled by American Academy of Ophthalmology, April 2011). Because of the impervious nature of the ocular surface and lacrimal clearance, targeting the drug to the appropriate site of action is usually one of the greatest challenges in drug delivery (Gipson, 2007; Singh et al., 2011; Gaudana et al., 2008). For a successful pharmacotherapy, the drug should be present at the target site (cornea or conjunctiva) in a therapeutically effective concentration for a predefined period of time. The bioavailability of the drug depends upon the physico-chemical properties of the drug, the target tissue, drug absorption, distribution, elimination, and the drug delivery system. For most of the drugs, the pharmacokinetics and efficacy is well understood, however, delivery of the drug to the target site in a therapeutically effective concentration for a stipulated period of time is the challenge.
1. Ocular Drug Delivery
Generally, medication to the eye is delivered by topical ocular, systemic, and intraocular or periocular injections. Ocular diseases are commonly treated with a topical application of drug solutions (i.e. eye drops or ointments). These conventional dosage forms account for nearly 90% of currently available marketed formulations because of their simplicity, safety and acceptance by patients. However, ocular surface barriers can limit the drug absorption and its bioavailability in the eye. Topical ocular drug administration is accomplished by eye drops, but they have only a short contact time on the eye surface. Typically, <5% of the drug can penetrate through the cornea and reach the intraocular tissue. As a consequence, multiple administrations of eye drops are required for therapeutic effect (Sultana et al., 2007; Kuno and Fujii, 2011; Gaudana et al., 2010). Administration of eye drops several times in a day result in high and low drug concentration profiles, i.e. high concentration in the toxic range and low concentration in the ineffective range, in addition to a short window of therapeutically effective range (FIG. 10). The major disadvantage of these conventional dosage forms is that they exhibit extremely low bioavailability. The drug contact time and the duration of drug action have been improved by developing gel formulations, ointments, and ocular inserts. Systemically administered medications, in general, have limited ocular penetration and may require high peripheral drug levels with the potential of toxicity. Ocular or periocular injection of medication is traumatic and invasive, is rapidly diluted, and may require repeat procedures for adequate drug levels.
2. Ocular Pharmacokinetics and Drug Transport Across the Ocular Surface
Ocular pharmacokinetic studies are straightforward in vivo experiments analyzing the drug concentrations in the ocular tissues after local or systemic drug administration with or without special delivery systems. Another class of ocular pharmacokinetics includes drug permeability studies in which relationships between physicochemical drug properties and permeability are evaluated (Mannermaa et al., 2006). All these studies are clinically driven, to provide basic information about the ocular pharmacokinetics, without aiming to understand the mechanisms of permeation in the relevant barriers. However, a thorough understanding of the drug molecular diffusion across cornea and conjunctiva is crucial for the development of clinically translatable nano drug delivery systems.
Passive Diffusion of Drug Molecules in the Corneal Epithelium
Topically delivered drug (eye drops or ointments) enters the anterior chamber of the eye by diffusion through the cornea. Approximately a 20 to 60 min lag time is required for the drug to reach the aqueous humor. Lag time is equal to the rate of diffusion of a drug molecule across the cornea. In general, the amount of drug diffusing through the cornea is linearly proportional to its concentration in the tear film. The decline of drug concentration in the tears (hence the concentration of drug penetrating the cornea) follows first order kinetics and the rate depends on the rate of dilution by freshly secreted tears (FIG. 10). In humans, the half-life of a single 20 μl drop of drug solution ranges from 2 to 20 minutes. Hence, only 1 to 5% of the topically applied drug ever reaches the anterior chamber and the rest of the drug will be cleared by the tear film, nasolacrimal drainage system, and systemic absorption from the nasal and gut mucosa (Urtti, 2006).
Diffusion of drug molecules from the tear fluid to cornea is controlled by the residence/contact time of the delivery system on the ocular surface and drug permeability in the cornea. Drug permeability in the cornea is due to passive diffusion or by active transport. Active transport require expression of transporters in the corneal epithelium. Passive diffusion is not dependent on transporter proteins, but it is rather driven by the physical chemical parameters that determine the partitioning and diffusion of the drug molecule in the lipid bilayers of the cell membrane (Mannermaa et al., 2006). Cornea is a fairly tight barrier for drug absorption: permeability of the corneal epithelium is 10−7-10−5 cm/s and the ocular drug bioavailability after topical ocular administration is less than 5% even for small lipophilic molecules (Urtti et al., 1990). The corneal epithelium is a well-recognized barrier to drug absorption (Maurice and Mishima, 1984). The role of corneal epithelium as a barrier and drug depot for the slow release of lipophilic molecules has been demonstrated by Sieg and Robinson (1976). Thus, corneal epithelium can function as a barrier to hydrophilic molecules or as a barrier and depot for small lipophilic molecules. For the smooth permeation of lipophilic drug across the cornea, the log D values should be 2-3 and the permeability decreases with higher log D value (>3) due to strong binding to the lipophilic epithelium.
Active Transport of Drug Molecules in the Corneal Epithelium
Corneal permeability of the drug molecules is sum of the passive diffusion and active transport, and the effect of active transport depends on the extent of passive diffusion. In the corneal epithelium, active transport of hydrophilic drug molecules will be significantly higher than the lipophilic drugs because of the low passive diffusion of hydrophilic molecules. Since the transporter expression is significant on the apical surface of the corneal epithelial cells, active transport of hydrophilic drug molecules across the corneal epithelium will be higher than lipophilic drug molecules. According to the Michaelis-Menten kinetics, active transport of the drug molecules depends on the drug concentration, its affinity to the transporter (Km), and the expression level (i.e. maximum capacity) of the transporter in the membrane (Vm) (Mannermaa et al., 2006).
Physicochemical Properties of the Drug
The drug molecules diffuse across the corneal epithelium via transcellular or paracellular pathways. Generally, lipophilic drugs diffuse via transcellular pathway while hydrophilic drugs diffuse by paracellular pathway through the intercellular spaces (Borchardt, 1990). In the case of topically applied drugs, passive diffusion via transcellular or paracellular pathway along the concentration gradient is preferred. The rate of drug permeation in cornea is affected by physicochemical properties of the drug, such as molecular size, shape, charge, degree of ionization, solubility, and lipophilicity (Schoenwald and Huang, 1983; Grass and Robinson, 1988; Liaw and Robinson, 1992; Huang et al., 1989; Rojanasakul et al., 1992; Liaw et al., 1992; Sieg and Robinson, 1977; Maren and Jankowski, 1985; Brechue and Maren, 1993). Lipophilic corneal epithelium is the rate limiting barrier for the diffusion of highly hydrophilic drugs, while partitioning from the corneal epithelium to the hydrophilic stroma is rate limiting for highly hydrophilic drugs that determines corneal permeability. The rate limiting barrier is located at the very surface of the epithelium for moderately lipophilic β-blockers while the whole corneal epithelium is the barrier for hydrophilic compounds (Shih and Lee, 1990). Diffusion of an ionizable drug depends on the chemical equilibrium between the ionized and unionized drug in the tear fluid (Friedrich et al., 1993). The unionized drug molecules diffuse through the lipid membrane more easily than the ionized form. For example, transcorneal penetration of free pilocarpine base was 2-3 times greater than that of the ionized form in vitro (Francouer et al., 1983; Mitra and Mikkelson, 1988).
3. Barriers and Challenges in Ocular Drug Delivery
Delivery of drugs to the anterior segment of the eye in therapeutically effective concentrations is essential for the treatment of infections and inflammations of the cornea and the ocular surface. Cornea and conjunctiva are the major routes of anterior segment drug absorption, however factors, such as impermeability of the corneal epithelium, tear dynamics, momentary residence in the fornix conjunctiva and systemic absorption affect the bioavailability and therapeutic efficacy of a drug. Improving the bioavailability by increasing the drug permeability and absorption in the eye is a great challenge. It is also important to achieve an optimal drug concentration at the target site.
Corneal Barrier
The healthy cornea is a transparent primary lens of the eye. The corneal diameter is about 11.7 mm. The corneal epithelium is the most anterior layer of about 50 μm in thickness. Apical corneal epithelial cells are flat and form tight junctions in the intercellular spaces which act as an effective barrier not only to most microorganisms but also to therapeutic drugs. These tight junctions are located only in the most apical surface cell layers and they provide the diffusional barrier for drug absorption from the tear fluid to the anterior chamber of the eye (Reinsten et al., 1994; Hitzenberger et al., 1994; Grass and Robinson, 1988). Corneal epithelium is the major limiting barrier in the corneal drug absorption and transcorneal drug permeation (Maurice and Mishima, 1984).
Conjunctival Barrier
The conjunctiva is a vascularized mucus membrane that covers the inner surface of the eyelids and covers the anterior part of the sclera. Tight junctions of the superficial conjunctival epithelium are the main barrier for drug penetration across conjunctiva, although the conjunctival epithelium has wider intercellular spaces than the cornea. The conjunctival epithelium also covers a much larger surface area (16-18 cm2) compared to that of the cornea (1 cm2) (Dartt et al., The Biology of the Eye). Because of the relative leakiness of the conjunctival epithelium, rich blood flow, and large surface area, conjunctival uptake of a topically applied drug from the tear fluid is typically an order of magnitude greater than corneal uptake. However, due to the presence of blood capillaries and lymphatics in the conjunctiva, most of the drug will be lost into the systemic circulation, thereby lowering ocular bioavailability. Because of the systemic drug absorption following conjunctival uptake even substantial enhancement of the drug residence times by the ocular insert drug delivery systems in the conjunctival sac may not always result in significant improvements in ocular drug absorption (Newell, 1986; Ahmed et al., 1987). Taken together, cornea and conjunctiva are rate-limiting barriers for the drug absorption in the anterior segment of the eye.
Tear Dynamics
The tear film acts as a dynamic barrier due to a high turnover rate and gel-like mucus layer. The basal tear flow is ˜1.2 μl/min (0.5-2.2 μl/min) and reflex stimulation can increase lacrimation up to 300 μl/min (Dartt et al., The Biology of the Eye; Mishima et al., 1966). Topical administration of eye drops stimulate reflex tearing and the drug is quickly washed away by the tear film after application. Gel forming mucus, such as MUC5AC creates a hydrophilic layer that interfaces with the glycocalyx of the ocular surface epithelium and clears cell debris, foreign bodies, and pathogens. Approximately 2-3 μl mucus is secreted daily and acts as a barrier to drug adsorption (Gipson and Argueso, 2003).
Drug Elimination by the Nasolacrimal Drainage System from Tear Fluid
Because the residence tear volume of the eye is generally 7-10 μl, most topically administered solutions are washed away within 15-30 seconds of application (de la Fuente et al., 2010). Topically administered drugs are mainly eliminated from the precorneal tear fluid by reflex tearing and drainage into the nasolacrimal system. The normal commercial eye dropper delivers a drop of ˜40 μl. When an eye drop is instilled, the human eye momentarily contains ˜30 μl volume, but the instilled solution is rapidly removed by spillage from the conjunctival sac or loss through the puncta to the lacrimal drainage system until the tears return to their normal volume (7 μl) (Lederer and Harold, 1986; Zaki et al., 1986). If the volume of an eye drop is decreased to 5-10 μl and the applied dose is kept constant by increasing the concentration, the ocular bioavailability of the drug can be improved (Chrai et al., 1973). Ocular administration of irritating drugs increases the drug loss from the precorneal area to a further extent due to reflex lacrimation (Meseguer et al., 1993; Craig, 2002).
Systemic Absorption
The goal of ophthalmic drug delivery systems has traditionally been to maximize ocular drug absorption rather than to minimize systemic absorption (Urtti et al., 1990). After instillation of an eye drop, less than 5% of the instilled dose is absorbed into the eye, whereas systemic absorption is often more than 50% of the instilled dose (Urtti and Salminen, 1993; Lee et al., 1993). The main sites for systemic absorption are conjunctiva and nasal mucosa. Systemic absorption of ocularly applied drugs is often nearly complete and could lead to systemic side effects varying from mild to life-threatening events. In the case of ophthalmic drugs that may cause systemic side effects, the drug delivery system must deliver the drug only to the target tissue in a controlled release fashion thus minimizing the systemic absorption of the drug. Clinical administration of a topically applied drug is often limited by its ocular/systemic side effects, such as tearing, blurring of vision, and irritation (Shell, 1984). Since irritation is related to the drug concentration on the ocular surface tissue, a controlled release drug delivery system can minimize irritation and enhance patient compliance.
4. Nano Drug Delivery Strategies
Although the conventional solution and suspension drug formulations are still the most frequently used dosage forms, several new drug delivery systems have been developed to minimize ‘peak and valley’ effects and maintain drug concentration at an effective level for a prolonged periods of time (Vandervoort and Ludwig, 2007). Recent advances in topical ocular drug delivery have ranged from improvement of eye drops to emulsions, liposomes, lipid nanoparticles, and ocular inserts (Sultana et al., 2011; Kapoor and Chauhan, 2008; Mahmoud et al., 2008; Souto et al., 2010; Li et al., 2008; Seyfoddin et al., 2010; Mack et al., 2009). All these endeavors aim at enhancing drug bioavailability by providing prolonged or sustained delivery to the eye or by facilitating trans-corneal penetration. Nonetheless, very few alternative drug delivery systems have successfully appeared on the market: currently, 95% of products are delivered via the traditional eye-drop bottle (Table 1).
TABLE 1Representative commercial ocular drug delivery formulationsActiveProductPharmaceuticalNameIngredientFormulationCompanyIndicationsStatusRestasisCyclosporin AEmulsionAllerganSevere dry eyeMarketed indiseaseUSARefresh dryEmulsionAllerganDry eyeMarketed inEye therapydiseaseUSADurezolDifluprednateEmulsionAlconInflammationMarketed inUSACationormCationicNovagaliMild dry eyeMarketed inEmulsiondiseaseEuropeSoothe XPEmulsionBausch & LombDry eyeMarketed inEmollientdiseaseUSATear AgainVitamin ALiposomeOptimaDry eyeMarketed inPharmazeutischediseaseUSA
TABLE 2Nanoparticulate drug delivery systems used in ophthalmic researchDrugNanoparticulate SystemResultReferencesOligonucleotidesLiposomesBetter control of release rate[69]AcetazolamideLiposomesProduced a marked decrease in IOP[70]Pilocarpine HClLiposomesIncreased mitotic response and ocular[71]bioavailability of the drugInulinLiposomesIncreased ocular concentration of the drug[72]GCVAlbumin NanoparticlesIncreased antiviral aciivity against human[73]cytomegalovirus (HCMV) infectionPilocarpineMicroemulsionsDecreased IOP by 25%[74]AmikacinNanoparticlesImproved delivery of drug to cornea and[75]aqueous humourPilocarpinePoly(butyl)-cyanoEnhanced mitotic response and decrease[76]acrylate Nanopartilcesin IOP by 22%FlurbiprofenAcrylate PolymerIncreased drug levels in aqueous humour[77]NanosuspensionsCyclosporinChitosan NanoparticlesEnhanced delivery to external ocular[78]tissueDexamethasoneMicroemulsionsEnhanced bioavailability in aqueous[79]humourPilocarpineDendrimersProlonged miotic activity[80]nitrate,TropicamideDexamethasoneHP-β-CDEnhanced solubility, permeability, and[81, 82]corneal bioavailability
5. Nano Drug Delivery Systems
Nano drug delivery systems such as nanoparticles, liposomes, micelles, and dendrimers have been developed with the aim of enhancing ocular drug delivery (Singh et al., 2011; GAudana et al., 2008; Sultana et al., 2007; Kuno and Fujii, 2011; Gaudana et al., 2010). These systems are claimed to provide a prolonged residence time at the ocular surface, minimizing the effect of natural eye clearance systems. It has been argued that, when combined with controlled drug delivery, it should be possible to provide drug therapeutic levels for a prolonged time at the site of action. Nano and microparticles have been developed for systemic drug delivery however, not much progress has been made in the development of nanotechnology based drug delivery systems for treating ocular diseases. Recently, emulsions, micro and nanoparticles have been used in ocular drug delivery with limited success (Diebold and Calonge, 2010; Gershkovich et al., 2008; Choy et al., 2008; Chang et al., 2011). Some of the currently developing nano particulate drug delivery systems are listed in Table 2. Even the nanoparticle suspensions were also rapidly cleared from the eye leading to limited drug efficacy. Micro-/nanoparticle-based delivery systems are easy to prepare, but exhibit limitations, such as: low drug loading, burst drug release kinetics, and clumping of the particles in the fornix and along margins of the eyelids. Also, due to the very short period of drug release (˜1-3 h), the therapeutic efficacy is very limited, requiring multiple administrations. To improve the drug retention time in the eye, in situ gel forming systems have been developed (He et al., 2008). A solution containing drug upon instillation as eye drops undergo sol-to-gel phase transition on the eye surface. The in situ formed gels are expected to hold the drug for a longer period of time thus enhancing its bioavailability. However, these in situ forming gels could increase the drug retention times to a few hours. Drug-loaded contact lenses have been developed to improve the drug retention time in the eye (Gulsen and Chuauhan, 2004; Singh et al., 2011). Because contact lenses are in constant contact with the cornea, drug-loaded contact lenses are expected to enhance the drug retention times to more than 30 min. The problem with these systems is that most of the drug diffuses out in an hour or more. As a further advancement, contact lenses loaded with drug filled liposomes, micelles, microemulsions or nanoparticles have been developed (Garhwal eet al., 2012; Peng and Chauhan, 2011; Yanez et al., 2011). These approaches have improved the drug retention times for a few hours, however are not well suited for extended release for a day to a week. Recently, drug-loaded PLGA films were encapsulated inside the contact lenses for the long-term release of econazole (Ciolino et al., 2011). Although, these systems could deliver the drug for up to a month, they are limited by reduced transparency and low oxygen permeability because of the thick PLGA film (Jung and Chauhan, 2012). Also, because of the biodegradable nature of PLGA, these contact lenses cannot be packaged in PBS. In summary, all these systems, although could extend the drug retention times by a few hours, they could not release the drug in a controlled release fashion for extended periods of time. Hence, there is a strong need for the development of programmable drug delivery systems with high drug content and long term drug release attributes.
6. Gaps in the Present Ocular Drug Delivery Systems
Ocular drug delivery can be reduced to the simple goal of getting the right pharmacologic agent at the appropriate therapeutic dose to the target ocular tissue by a method that does not damage healthy tissue. In the treatment of ocular disease, however, this simple goal becomes more challenging because of the highly sensitive ocular tissues and the ocular surface barriers to drug penetration as described above. The challenge is to delicately circumvent these protective ocular surface barriers and deliver the drug to the target site (cornea or conjunctiva) without causing permanent tissue damage. Despite sustained efforts, the development and optimization of new nano drug delivery systems have been very slow.
To improve the therapeutic efficacy of ophthalmic drugs, the drug delivery system must encompass the following attributes: (i) Increase drug residence time on the ocular surface; (ii) Increase the drug absorption; (iii) Improve the bioavailability of the drug; (iv) Minimize systemic absorption of the drug; (v) Improve the local tolerability of the drug delivery system and (vi) Patient compliance. The major challenge to address in drug delivery to the ocular surface is how to localize drug action within the target site and maintain therapeutic drug levels while minimizing systemic effects. Also, the issue of patient compliance must be seriously considered in ocular drug delivery. If a drug must be given every hour for a week, for example, to reach therapeutic tissue concentrations when treating a chronic disease, it is very unlikely to be given consistently, if at all.
Embodiments of the present disclosure satisfy a long-felt need in the art to provide a controlled release ocular drug delivery system that can release the drug in therapeutically effective concentrations for longer duration of time (for example, from a day to a week).